The objective of this project is to understand the neural systems involved in the attention deficits in fragile X syndrome (FXS), so that effective treatments can be devised. The attention impairment characteristic of FXS are more severe than would be expected for their'I.Q, We hypothesize that defects in three different brain systems interact to produce these extreme attention difficulties. First, impairment of executive function ha been shown to contribute to attention deficits in FXS. Second, abnormal processing of sensory information likely impairs attention as well as leading to over arousal that impairs attention. Finally, abnormalities in the hypothalamic pituitary adrenal axis likely contribute to arousal and lower cognitive function. We will use the newly developed and validated 5-arm maze attention measure. Effects of distracting stimuli on performance on this task will also be explored. Active avoidance is a task on whichWe have found profound effects of attentional and emotional factors. As parameters of this task can be varied systematically to determine the nature of the learning problem, this task will be used to determine the impact of the sensory and emotional difficulties on cognitive performance. The HPA axis has not been studied in the Fmr1 KO mouse, but humans with FXS return to basal corticosterone levels more slowly after stress than do controls, a result that would be predicted by the finding from Eberwine and Greenough that FMRP binds to the glucocorticoid receptor (GR), resulting in a 25% decrease in GR levels Inthe hippocampus in the Fmr1 KO mouse. We will conduct a thorough examination of the corticosterone daily rhythm, response to and recovery from stress, In other animal models of reduced GR effects on the HPA axis have been difficult to predict, so brain and adrenal expression of markers for the entire axis (GR, MR, CRF, ACTH, POMC corticosterone) will be examined, as expression of these molecules in the brain can have profound effects upon cognition and behavior. All of these aims build to the final aim, When we have good measures of attention and cognitive performance and know the abnormalities in the HPA axis, we can select drugs likely to impact the three systems we hypothesize to be involved in the attention deficits in FXS. Individual md combination tests of these drugs will determine the relative roles of each of these systems, and lead to [unreadable]-,-combination treatments for this Important problem In FXS.